The pharmaceutical and biotechnology industries face an important challenge of improving the therapeutic efficacy of drugs and drug-candidates. For the administration of certain types of pharmaceuticals conventional dosage forms are not always very suitable. For instance, many of the most potent drugs and drug candidates have a low solubility in water and are thus not adequately absorbed by the body; small drugs suffer from a fast renal clearance and biopharmaceuticals undergo rapid enzymatic degradation.
Various approaches have been used to improve the pharmacokinetic and pharmacodynamic properties of such drugs, one of them being conjugating the drug to natural or synthetic polymers and another one being the formation of solid dispersion and solid solutions using a polymer excipient.
Poly(ethylene glycol) (PEG) is most often used as a carrier for the conjugation of drugs. By increasing the molecular weight of a pharmaceutical through PEGylation, several significant pharmacological advantages over the unmodified form arise, such as an improved drug solubility, extended circulating half-life, reduced immunogenicity, increased drug stability and an improved protection against proteolytic degradation. PEG improves a drug's therapeutic efficacy by increasing the drug's hydrodynamic radius, thereby (partially) shielding it from interactions with the body, including the immune system and proteolytic enzymes. Especially this latter shielding property is the main driving force for the success of PEG, compared to many other water soluble polymers, which is believed to result form the good hydration of PEG.
Despite the common use of PEGylation there are several disadvantages associated with its use. Sometimes, hypersensitivity and the formation of PEG antibodies is observed. It is also observed that when PEG with high molecular weights is used, it accumulates in the liver, leading to the so called macromolecular syndrome. The chain length of the PEG molecules may be reduced under the influence of enzymes, such as P450 or alcoholdehydrogenase, giving rise to toxic side products.
With respect to small therapeutic molecules it is often observed that with PEG only a relatively low drug loading can be achieved due to the presence of merely one or two hydroxyl terminal groups that can be activated. Furthermore, orthogonal functionalization of PEG or PEG dendrons with the therapeutic moiety, detection moiety or targeting moiety is not readily possible.
Furthermore, it is relatively difficult and hazardous to prepare PEG as explosive and highly toxic condensed ethylene oxide monomers are required. In addition, PEG has a limited storeability, i.e. an antioxidant is required for storage in order to avoid peroxide formation.
Therefore, there is a need for well defined, non-immunogenic and non-toxic polymer carriers for drug delivery.
For fulfilling this purpose, polyoxazolines (POX) seem to be promising candidates. They typically offer the advantages of a straightforward preparation, a good stability, a low toxicity and immunogenicity, large loading capacities, good hydrophilic properties and good protein repellent effects.
However, an important drawback of commercially available synthetic polymeric materials like PEG and POX lies in the fact that they are not very uniform in that they comprise a broad mixture of polymers of various chain lengths. This heterogeneity of molecular weight (‘polydispersity’)—or ‘dispersity’ as nowadays recommended by the IUPAC)—is an inherent result of the polymer's production process. Small impurities in the reaction mixture cause side-reactions during polymerization that lead to preliminary chain termination.
It is readily understood that for biomedical applications it is highly desirable to employ well-defined, chemically homogeneous materials. As far as high molar mass polymers are concerned it is generally desirable to minimize the level of low molar mass polymer fragments. In other words, it is important to reduce the dispersity of polymers for biomedical applications as much as possible. This goal is particularly difficult to achieve, since biomedical applications usually require high molecular weight polymers and dispersity increases with increasing molar mass, especially for cyclic imino ether polymers as during preparation of these polymers intrinsic chain transfer occurs by so-called beta-elimination.
WO 2008/106186 describes a terminally activated polyoxazoline (POX) compound comprising a POX polymer having a single active functional group on a terminal end thereof, said functional group capable of reacting with a group on a target molecule to create a target molecule-POX conjugate. In the international patent application it is observed that it is frequently necessary for commercial development of polymer-modified drugs to utilize polymers with molecular weights (MWs) as high as 40,000 Da or higher and with molecular weight distributions or polydispersities (PDs) of less than 1.1, but that there has been a great deal of work showing that MWs and PDs in the above range cannot be achieved for POX with conventional techniques. WO 2008/106186 describes methods for obtaining POX derivates with low PD values involving purification of the reaction mixture by anion exchange chromatography. Example 36 describes a polyethyloxazoline polymer with a MW of 15.200 Da and a PD of 1.09.
US 2009/156782 describes a method for preparing monodispersible homo- and random copolymers of 2-ethyl-2-oxazoline and 2-iso-propyl-2-oxazoline. The method described by US 2009/156782 involves dialysis purification of the reaction mixture against water. Referential example 1 describes the preparation of a poly(2-isopropyl-2-oxazoline) polymer with a molecular weight (Mn) of 9700 (DP=86) and a degree of dispersion (Mw/Mn) 1.02.
U.S. Pat. No. 3,326,929 describes treating oxazoline monomers with acid chlorides or acid anhydrides in order to satisfactorily purify said oxazoline monomers so that polymerization can be effected by cation-active catalysts without chain breakage. The exact Mn and dispersity of the resulting polymers are not reported.
U.S. Pat. No. 4,281,137 describes the removal of residual amounts of water and color-causing impurities from 2-oxazoline compounds for attenuating the undesirable effect of these impurities on the color of an oxazoline polymer. This is achieved by reacting the monomers with chlorosilanes or phosphites. The US patent does not contain any information on the Mn and dispersity of the resulting polymers.
T. X. Viegas et al. (2011) Bioconjugate Chem. 22, 976-986 describes a specific procedure for the synthesis of 5 kDa and 10 kDa polyethyloxazoline polymer with a dispersity of less than 1.1.